Is ASB5 p.Ile259Thr (c.776T>C) pathogenic?

ASB5 p.Ile259Thr (c.776T>C) is classified Likely benign in ASB5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-25). AlphaMissense: likely benign (0.1252); Ultra-rare (popmax 0.0329%, mid).

How common is ASB5 p.Ile259Thr (c.776T>C) in the general population?

ASB5 p.Ile259Thr (c.776T>C) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

What do computational predictors say about ASB5 p.Ile259Thr (c.776T>C)?

AlphaMissense predicts likely benign (score 0.1252) — an in-silico prediction, not a clinical call.

ASB5 p.Ile259Thr

c.776T>C · VCV3434954

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1252 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1252	likely benign
REVEL	0.197	benign-leaning
SaProt	LLR -6.50	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP -3.1, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 54 kb · p 0.91 · regional, not allelic
Overall
CADD	19.33	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0329% Middle Eastern · 2/6,084 alleles

Filtering AF 0.0058% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00267%

Overall 0.0031% 50/1,613,970 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,042
European (non-Finnish)	0.0039%	25,652
African / African-American	0.00133%	74,916
South Asian	0.0011%	91,082

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: ASB5
Protein: p.Ile259Thr
Coding: c.776T>C
MANE Select: NM_080874
Type: single nucleotide variant
Location: chr4:176216904 (GRCh38)
Gene constraint: LOEUF 1.317 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.93

Full ASB5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ASB5 p.Ala175Thr Uncertain significance ★ ⚠ same type
ASB5 p.Ala176Ser Uncertain significance ★ ⚠ same type
ASB5 p.Ala51Pro Uncertain significance ★ ⚠ same type
ASB5 p.Ala69Val Uncertain significance ★ ⚠ same type
ASB5 p.Ala77Ser Uncertain significance ★ ⚠ same type
ASB5 p.Ala85Thr Uncertain significance ★ ⚠ same type
ASB5 p.Arg302Gln Uncertain significance ★ ⚠ same type
ASB5 p.Asn142Lys Uncertain significance ★ ⚠ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/asb5-p-ile259thr (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown